Established Strategy Research Articles

Conversion from radical esophagectomy to definitive chemoradiotherapy after neoadjuvant chemotherapy for advanced esophageal squamous cell carcinoma: Treatment options based on chemotherapy response.

408 Background: Radical esophagectomy after neoadjuvant chemotherapy (NAC) is the established strategy for resectable advanced esophageal cancer. However, some patients convert to definitive chemoradiotherapy (dCRT) after NAC due to reasons such as their wishes or disease progression, and their prognosis remains uncertain. We aimed to investigate the prognosis of patients who converted to dCRT. Methods: Patients who underwent NAC for resectable advanced esophageal squamous cell carcinoma between 2006 and 2020 were enrolled retrospectively. The prognostic impact of subsequent treatment after NAC, planned surgery or conversion to dCRT, was compared. Results: We analyzed 686 patients, 70 who converted to dCRT (dCRT group) and 616 who underwent surgery (Surg group). The dCRT group had a poorer prognosis than the Surg group, with more advanced tumors and poorer response to NAC. Therefore, further analysis was conducted by categorizing patients as Responders (complete or partial response) and Non-responders (stable or progressive disease) to NAC. Among Responders in the dCRT group, 76.7% achieved a complete response, and the 5-year esophageal preservation survival rate was 66.9%. The 5-year survival rates for Responders were 77.5% and 71.3% in the dCRT and Surg groups. Multivariable analysis showed that dCRT did not worsen prognosis ( P = .706, hazard ratio = 1.13; 95% confidence interval, 0.59 to 2.16). Conversely, in Non-responders, dCRT had a significantly poorer prognosis, with 5-year survival rates of 22.3% and 45.1% in the dCRT and the Surg groups (P < .001). Conclusions: For patients responding to NAC, conversion to dCRT is considered a potential treatment option. The possibility of chemoselection has been suggested in the choice of treatment for esophageal squamous cell carcinoma.

Correlation between parathyroid adenoma volume and perioperative outcomes inprimary hyperparathyroidism: Does the size matter?

Primary hyperparathyroidism (PHPT) due to a parathyroid adenoma stands as one of the most prevalent endocrinological disorders, with focused parathyroidectomy being the established therapeutic strategy. This study aims to investigate whether the volume of the pathological gland influences perioperative outcomes and postoperative morbidity. A retrospective analysis was conducted on data from 141 patients who underwent focused parathyroidectomy for PHPT at the University Hospital of Basel between 2007 and 2022. A total of 141 patients underwent surgery, with a mean age of 57.2years and prevalence of women (64.5%).The volume of the lesion was divided into three groups (low < 1ml, middle 1-1.99ml, large > 2ml) based on pathological specimen analysis. Preoperative calcium and parathyroid hormone (PTH) values were significantly higher in the large volume group compared to the low volume group (p < 0.05), while phosphate and vitamin D values were significantly lower (p < 0.05). A comparison of adenoma volume in symptomatic patients with asymptomatic patients revealed no statistically significant difference (p = 0.845) and the volume of the gland of any group did not influence the length of the operation (p = 0.173) and the perioperative morbidity (p = 0.108). Compared to a volume of less than 1ml, a parathyroid gland volume greater than 2ml was associated with higher preoperative PTH and calcium levels and lower phosphate and vitamin D levels. The volume of the parathyroid gland does not seem to impact the clinical manifestations, or the incidence of perioperative complications.

Targeting fucosyltransferase FUT8 as a prospective therapeutic approach for DLBCL

Diffuse large B-cell lymphoma (DLBCL) is characterized by its aggressive nature and resistance to standard chemotherapy, necessitating the development of new therapeutic approaches. The emergence of natural products and their derivatives has notably influenced cancer treatment, making morusinol, a medicine-derived monomer, a promising candidate. Here, we showed that morusinol exerted antitumor effects on DLBCL in vitro by inducing apoptosis and cell cycle arrest. Impressively, morusinol treatment exhibited potent tumor growth inhibition in vivo, proving both well-tolerated and safe in mouse models. Moreover, our investigation identified FUT8, a fucosyltransferase, as a potential target for morusinol. FUT8’s role as an oncogene in DLBCL and its correlation with poor survival further underscored its significance. Furthermore, our screening efforts involving clinical and preclinical drugs unveiled a compelling synergistic effect between chidamide and morusinol. Additionally, morusinol’s ability to hinder M2-like polarization of tumor-associated macrophages suggested its potential in immune response modulation within DLBCL. Collectively, morusinol showcased substantial promise as an anti-tumor agent for potential clinical application in DLBCL management, potentially augmenting established therapeutic strategies. Moreover, our findings offered promising prospects for natural products to effectively leverage its therapeutic advantages.Working model: The role of Morusinol in treating DLBCL.

Lifestyle Factors and the Microbiome in Urolithiasis: A Narrative Review

Urolithiasis represents one of the most common urologic diseases, and its incidence demonstrates, globally, an increasing trend. The application of preventive measures is an established strategy to reduce urolithiasis-related morbidity, and it is based mostly on the adaptation of lifestyle factors and pharmacotherapy. Furthermore, other research areas demonstrate promising results, such as the research on the microbiome. In the current review, we searched for the latest data on lifestyle–based prevention and microbiome alterations in urolithiasis patients. The majority of the proposed lifestyle measures are already included in the urological guidelines, while additional factors, such as vitamin D supplementation, seem to have a putative positive effect. From the microbiome studies, several microbial composition patterns and metabolic pathways demonstrated an inhibiting or promoting role in lithogenesis. Up to the present, stone prevention has not shown satisfying results, which suggests that lifestyle measures are not adequate. Moreover, microbiome studies are prone to bias, since microbes are strongly affected by numerous clinical factors, while the analysis procedures are not standardized yet. Analysis standardization and data pooling from extensive registration of clinical and microbiome data are essential steps in order to improve the existing prevention strategy with targeted microbiome manipulations.

Primary adenocarcinoma of the lacrimal sac with 5-year recurrence-free survival after radiation therapy alone: a case report

Abstract Lacrimal sac tumors are rare, with approximately 800 cases reported worldwide; primary adenocarcinoma of the lacrimal sac is particularly rare. Although there is no established treatment strategy, surgical removal is generally performed. However, complete removal often requires extensive resection, including orbital exenteration and lateral rhinoplasty, which is highly invasive and creates significant cosmetic issues. Here, we report our experience with a 72-year-old woman with primary adenocarcinoma of the lacrimal sac with ethmoid bone invasion. She refused surgery and was treated with radiation therapy alone, totaling 70 Gy in 35 fractions. This is the first report of a patient with primary adenocarcinoma of the lacrimal sac who survived for 5 years without recurrence after radiation therapy alone. She experienced late radiation-related complications: the affected eye developed grade-3 retinopathy according to the common terminology criteria for adverse events, version 5.0, and secondary neovascular glaucoma. Cataract and vitreous surgery with retinal photocoagulation were performed. Her cosmetic appearance was maintained after all treatments were completed. Radiation therapy may be an effective treatment for primary adenocarcinoma of the lacrimal sac for patients who either refuse surgery or in whom surgery is not feasible.

Revered and Reviled: The Plight of the Vanishing Sea Cucumbers.

Sea cucumbers paradoxically suffer from being both highly prized and commonly disregarded. As an Asian medicine and delicacy, they command fabulous prices and are thus overfished, poached, and trafficked. As noncharismatic animals, many are understudied and inadequately protected. Despite presenting a rich diversity of life histories, members of this broad taxonomic group (class Holothuroidea) are often managed simply as "sea cucumbers" in fisheries worldwide. One cannot imagine fishes (class Pisces) being given the same universal treatment. Yet this may happen for species of sea cucumber that differ on the same fundamental level as tilapia and tuna. As more sea cucumbers reach an endangered status and wild populations become depleted to the point of collapse, critical questions arise about the relevance of established conservation and governance strategies. This article reviews the main threats faced by exploited sea cucumbers, outlines conservation and governance effectiveness, identifies gaps in knowledge, and explores management and research perspectives in the context of climate change and booming fisheries crime. We stress the perilous state of harvested sea cucumbers globally and the urgent need for action.

In vivo base editing extends lifespan of a humanized mouse model of prion disease.

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain. Systemic injection of dual-adeno-associated virus PHP.eB encoding BE3.9max and single guide RNA installing PRNP R37X resulted in 37% average installation of the desired edit, 50% reduction of PrP in the mouse brain and 52% extension of lifespan in transgenic human PRNP mice inoculated with pathogenic human prion isolates representing the most common sporadic and genetic subtypes of prion disease. We further engineered base editing systems to achieve improved in vivo potency and reduced base editor expression in nontargeting tissues, resulting in 63% average PrP reduction in the mouse brain from a 6.7-fold lower viral dose, with no detected off-target editing of anticipated clinical significance observed in either human cells or mouse tissues. These findings support the potential of in vivo base editing as one-time treatment for prion disease.

Seizing the opportunity to therapeutically address neuronal hyperexcitability in Alzheimer's disease.

Seizures in people with Alzheimer's disease are increasingly recognized to worsen disease burden and accelerate functional decline. Harnessing established antiseizure medicine discovery strategies in rodents with Alzheimer's disease associated risk genes represents a novel way to uncover disease modifying treatments that may benefit these Alzheimer's disease patients. This commentary discusses the recent evaluation by Dejakaisaya and colleagues to assess the antiseizure and disease-modifying potential of the repurposed cephalosporin antibiotic, ceftriaxone, in the Tg2576 mouse model. The use of established epilepsy models in Alzheimer's disease research carries the potential to advance novel disease-modifying treatments.

Modeling Fibrous Tissue in Vascular Fluid-Structure Interaction: A Morphology-Based Pipeline and Biomechanical Significance.

Modeling fibrous tissue for vascular fluid-structure interaction analysis poses significant challenges due to the lack of effective tools for preparing simulation data from medical images. This limitation hinders the physiologically realistic modeling of vasculature and its use in clinical settings. Leveraging an established lumen modeling strategy, we propose a comprehensive pipeline for generating thick-walled artery models. A specialized mesh generation procedure is developed to ensure mesh continuity across the lumen and wall interface. Exploiting the centerline information, a series of procedures are introduced for generating local basis vectors within the arterial wall. The procedures are tailored to handle thick-walled tissues where basis vectors may exhibit transmural variations. Additionally, we propose methods for accurately identifying the centerline in multi-branched vessels and bifurcating regions. These modeling approaches are algorithmically implementable, rendering them readily integrable into mainstream cardiovascular modeling software. The developed fiber generation method is evaluated against the strategy using linear elastostatics analysis, demonstrating that the proposed approach yields satisfactory fiber definitions in the considered benchmark. Finally, we examine the impact of anisotropic arterial wall models on the vascular fluid-structure interaction analysis through numerical examples, employing the neo-Hookean model for comparative purposes. The first case involves an idealized curved geometry, while the second studies an image-based abdominal aorta model. Our numerical results reveal that the deformation and stress distribution are critically related to the constitutive model of the wall, whereas hemodynamic factors are less sensitive to the wall model. This work paves the way for more accurate image-based vascular modeling and enhances the prediction of arterial behavior under physiologically realistic conditions.

Collective total synthesis of chartreusin derivatives and bioactivity investigations.

Capitalizing on Hauser annulation and Yu glycosylation, the chemical synthesis of chartreusin-type aromatic polycyclic polyketide glycosides has been investigated, culminating in the successful establishment of chemical approaches toward chartreusin derivatives with intricate chemical structures but promising bioactivities. Based on the chemical synthesis strategy, the first and collective chemical syntheses of chartreusin, D329C, and elsamicins A and B have been accomplished. The chemical strategy was featured by two complementary routes to secure chartarin 10-O-monosaccharide glycosides, the key intermediates in chartreusin derivative synthesis, as well as the highly stereoselective construction of the difficult glycosidic linkages. Through the synthetic investigations, viable donors and acceptors of 3-C-methyl-branched sugars were determined for the first time. Moreover, facilitated by the established chemical synthetic strategy, the cytotoxic activities of chartreusin derivatives against human cancer cell lines were assessed and profound antineoplastic effects for chartreusin and elsamicins A and B were recorded. Based on RNA-seq analysis, the underlying working mechanisms against ES-2 cells were investigated, and the appended sugar chain-determined function mechanisms were disclosed.

Merging halogen atom transfer, ring-expansion and oxidation by electron-rich arenediazonium salts: modular assembly of cyclohexenone derivatives.

As fundamental structural scaffolds in numerous natural products and pharmaceutical molecules, the construction of cyclohexenone architectures has remained a pivotal focus in organic chemistry. However, established strategies to synthesize cyclohexenone derivatives via Dowd-Beckwith ring-expansion reaction invariably involve the use of transition metals and photoirradiation. Herein, we present a novel transition-metal- and photoirradiation-free pathway to access such structures from α-iodomethyl β-keto esters with electron-rich arenediazonium salts as inexpensive radical initiators and oxidants under mild reaction conditions. The unique aspect of this reactivity is the integration of halogen atom transfer, ring-expansion, and oxidation in one-pot. Further investigation reveals that this method is applicable for modifying complex biologically active molecules, such as epiandrosterone derivatives.

Catalytic asymmetric photocycloaddition reactions mediated by enantioselective radical approaches.

The use of olefins in the construction of cyclic compounds represents a powerful strategy for advancing the pharmaceutical industry. Photocycloaddition has attracted significant interest from chemists due to its ability to exploit simple and readily available olefins along with their reaction patterns under mild conditions. Moreover, the sustainable and versatile pathways for generating highly reactive intermediates can greatly enrich both substrate diversity and reaction patterns. As a result, numerous photocycloaddition reactions have been successfully developed, particularly asymmetric [2+2], [3+2], and [4+2] photocycloadditions mediated by enantioselective radical approaches, achieving remarkable enantioselectivities. This review offers a comprehensive overview of this rapidly evolving field, organizing the discussion into three distinct reaction types that facilitate the construction of enantioenriched derivatives of cyclobutanes, cyclopentanes, and cyclohexanes. Emphasis is placed on analyzing and summarizing established strategies aimed at circumventing the challenges posed by racemic background transformations. Additionally, the exploration of asymmetric [3+2] and [4+2] photocycloaddition reactions will be interwoven with a detailed discussion of the various substrate types involved. This systematic framework seeks to enhance understanding of the strategies employed to manage the high reactivity of radicals while achieving high enantioselectivity. Importantly, it aims to guide readers in identifying uncharted radical-based cycloaddition pathways, which possess significant potential to broaden the diversity of complex cyclic molecules.

Force–Position Coordinated Compliance Control in the Adhesion/Detachment Process of Space Climbing Robot

Adhesion-based space climbing robots, with their flexibility and multi-functional capabilities, are seen as a promising candidate for in-orbit maintenance. However, challenges such as uncertain adhesion establishment, unexpected detachment, and body motion unsteadiness in microgravity environments persist. To address these issues, this paper proposes a coordinated force–position compliance control method that integrates novel adhesion establishment and rotational detachment strategies, integrated into the gait schedule for a space climbing robot. By monitoring the foot-end reaction forces in real time, the proposed method establishes adhesion without risking damaging the spacecraft exterior, and smooth detachment is achieved by rotating the foot joint instead of direct pulling. These strategies are dedicated to reducing unnecessary control actions and, accordingly, the required adhesion forces in all feet, reducing the possibility of unexpected detachment. Climbing experiments have been conducted in a suspension-based gravity compensation system to examine the merits of the proposed method. The experimental results demonstrate that the proposed rotational detaching method decreases the required pulling force by 65.5% compared to direct pulling, thus greatly reducing the disturbance introduced to the robot body and other supporting legs. When stepping on an obstacle, the compliant control method is shown to reduce unnecessarily aggressive control actions and result in a reduction in relevant normal and shear adhesion forces in the supporting legs by 44.8% and 35.1%, respectively, compared to a PID controller.

Hormonomics profiles revealed the mechanisms of cold stratification in breaking the dormancy during seed germination and emergence process of Polygonatum sibiricum Red

ABSTRACT Polygonatum sibiricum Red, known as Huangjing in Chinese, is a perennial plant valued in traditional Chinese medicine and is a nutritional food ingredient. With increasing market demand outpacing wild resource availability, cultivation has become essential for sustainable production. However, the cultivation of P. sibiricum is challenged by the double dormancy characteristics of seeds, which include embryo and physiological dormancy. This affected the germination of seeds and the establishment of seedlings. This study investigates the role of plant hormones in breaking seed dormancy and regulating germination and emergence in P. sibiricum. We found that cold stratification at 4°C for over 70 d significantly alleviates seed dormancy, associated with changes in endogenous hormone levels. Auxin, gibberellin, abscisic acid, cytokinin, salicylic acid, jasmonic acid, and ethylene were identified as key players in these processes. Exogenous applications of GA3 and 2-coumarate (2-hydroxycinnamic acid) significantly enhanced seed germination, while 6-BA and GA3 promoted corm growth and development. In conclusion, our research provides insights into the hormonal regulation of seed dormancy and germination in P. sibiricum, offering valuable strategies for improving cultivation practices. Further studies are needed to explore the specific mechanisms of hormone interactions and to develop optimized germination and seedling establishment strategies for this medicinally important plant.

Designing Si Anode in Sulfide-Based All-Solid-State Batteries: Insights from Established Strategies in Lithium-Ion Batteries

Designing Si Anode in Sulfide-Based All-Solid-State Batteries: Insights from Established Strategies in Lithium-Ion Batteries

Preventing, identifying and managing myocardial injury after non cardiac surgery - a narrative review.

There is mounting and convincing evidence that patients with postoperative troponin elevation, with or without any clinical symptoms, are at higher risk for both, short- and long-term morbidity and mortality. Myocardial injury after noncardiac surgery (MINS) is a relatively newly described syndrome, and the pathogenesis is not fully understood yet. MINS is now an established syndrome and multiple guidelines address potential etiologies, triggers, as well as preventive and management strategies. Surveillance in high-risk patients is required, as most MINS would otherwise be missed. There is no reliable and established preventive strategy, but several potentially avoidable triggers like hypotension, pain and anemia have been identified. Managing patients with MINS postoperatively includes minimizing triggers (such as hemodynamic abnormalities and anemia) that can continue the damage. Long-term pharmacologic strategies include beta-blockers, statins, antiplatelet agents, and anticoagulation. MINS affects up to 20% of surgical patients, remains clinically mostly silent, but is associated with elevated morbidity and mortality. A multidisciplinary approach, that includes involvement of anesthesiologists, for the prevention, diagnosis, and treatment of MINS is recommended.

Maternal Migration and Child Fostering Arrangements in Nairobi's Slums

Child fostering—children living apart from their biological mothers—is an established strategy to support children and families throughout Africa. Little is known about how fostering decisions might be influenced by maternal migration and place of residence when women move to urban slums, which are home to a sizable proportion of Africa's urban population. Using a mixed-methods approach, we triangulate in-depth interviews with birth histories collected in two slum settlements in Nairobi, Kenya, to explore the interconnections between maternal migration experience, slum residence, and child fostering decisions. Our quantitative results reveal substantial fostering of children among women in slum contexts, with fostering being significantly higher among children of migrant women, particularly those who have recently arrived. Qualitative findings suggest that migration acts as an important impetus to foster, as do transitions in women's romantic relationships, economic uncertainty, poor slum conditions, and desires to send children to rural areas for schooling. This novel finding on children's schooling is supported in quantitative analyses, which show that older school-age children are more likely than younger children to be fostered. This study highlights the central roles of maternal migration, economic and social precariousness, and place of residence in determining the fostering of children among mothers living in informal settlements.

Quantitative Coronary Angiography Guidance for Drug-Eluting Stent Implantation: A Narrative Review.

Percutaneous coronary intervention (PCI) using drug-eluting stents is an established strategy for the treatment of significant obstructive coronary artery disease. Evidence supports that intravascular imaging-guided PCI offers advantages over conventional angiography-guided PCI, though its use is limited, likely due to high costs. Angiography-guided PCI relies on visual estimation, leading to inter- and intra-observer variability and suboptimal outcomes. Quantitative coronary angiography (QCA) provides reliable information about vascular dimensions, overcoming these limitations. Poststenting postdilation with appropriately sized noncompliant balloons improves outcomes by increasing lumen area and reducing stent malapposition. We investigated the procedural details of each modality used to guide PCI and assessed the utility of QCA-guided PCI with routine postdilation when intravascular imaging is unavailable. A systematic search was conducted from inception to May 31, 2024, identifying nine randomized controlled trials (with over 500 patients) that compared outcomes of PCI guided by intravascular imaging versus conventional angiography or QCA. The findings indicate that intravascular imaging guidance significantly improves clinical outcomes compared to angiography guidance. Notably, QCA-guided PCI with routine postdilation yielded outcomes comparable to those achieved with intravascular imaging-guided PCI. QCA-guided PCI with routine postdilation may be a viable alternative for improving PCI outcomes, especially in settings where intravascular imaging is unavailable.

Engineering an Escherichia coli strain for enhanced production of flavonoids derived from pinocembrin.

Flavonoids are a structurally diverse group of secondary metabolites, predominantly produced by plants, which include a range of compounds with pharmacological importance. Pinocembrin is a key branch point intermediate in the biosynthesis of a wide range of flavonoid subclasses. However, replicating the biosynthesis of these structurally diverse molecules in heterologous microbial cell factories has encountered challenges, in particular the modest pinocembrin titres achieved to date. In this study, we combined genome engineering and enzyme candidate screening to significantly enhance the production of pinocembrin and its derivatives, including chrysin, pinostrobin, pinobanksin, and galangin, in Escherichia coli. By implementing a combination of established strain engineering strategies aimed at enhancing the supply of the building blocks phenylalanine and malonyl-CoA, we constructed an E. coli chassis capable of accumulating 353 ± 19mg/L pinocembrin from glycerol, without the need for precursor supplementation or the fatty acid biosynthesis inhibitor cerulenin. This chassis was subsequently employed for the production of chrysin, pinostrobin, pinobanksin, and galangin. Through an enzyme candidate screening process involving eight type-1 and five type-2 flavone synthases (FNS), we identified Petroselinum crispum FNSI as the top candidate, producing 82 ± 5mg/L chrysin. Similarly, from a panel of five flavonoid 7-O-methyltransferases (7-OMT), we found pinocembrin 7-OMT from Eucalyptus nitida to yield 153 ± 10mg/L pinostrobin. To produce pinobanksin, we screened seven enzyme candidates exhibiting flavanone 3-hydroxylase (F3H) or F3H/flavonol synthase (FLS) activity, with the bifunctional F3H/FLS enzyme from Glycine max being the top performer, achieving a pinobanksin titre of 12.6 ± 1.8mg/L. Lastly, by utilising a combinatorial library of plasmids encoding G. max F3H and Citrus unshiu FLS, we obtained a maximum galangin titre of 18.2 ± 5.3mg/L. Through the integration of microbial chassis engineering and screening of enzyme candidates, we considerably increased the production levels of microbially synthesised pinocembrin, chrysin, pinostrobin, pinobanksin, and galangin. With the introduction of additional chassis modifications geared towards improving cofactor supply and regeneration, as well as alleviating potential toxic effects of intermediates and end products, we anticipate further enhancements in the yields of these pinocembrin derivatives, potentially enabling greater diversification in microbial hosts.

State of the Science of Structural Stigma and LGBTQ+ Health: Meta-Analytic Evidence, Research Gaps, and Future Directions.

While public health practitioners and scholars have long theorized that structural forms of stigma shape the health of disadvantaged groups, they have frequently bemoaned the lack of research on this topic. A unique opportunity to address this lacuna occurred in the past two decades, with the advent of dramatic changes in laws, social attitudes, and other structural manifestations of stigma surrounding LGBTQ+ individuals. In a review of this literature, we conducted a meta-analysis of LGBTQ+ structural stigma and health, finding an effect size comparable to several other well-established macrolevel risk factors for poor health (e.g., income inequality, racial residential segregation, neighborhood socioeconomic status). In addition, we enumerated a range of established methodological strategies that studies have used to strengthen inferences; these strategies include documenting result specificity (i.e., structural stigma is unrelated to the health of cisgender heterosexuals), addressing alternative explanations (e.g., social selection), and triangulating evidence across multiple methods, measures, and health outcomes. We offer suggestions for future research to advance this rapidly expanding field, including identifying sources of unexplained heterogeneity in the structural stigma-health association. Finally, we discuss implications for other marginalized groups and for public health interventions and policies to reduce LGBTQ+ health disparities.